微生物群驱动的Li-Fraumeni综合征肿瘤生长调节：胆汁酸作为关键介质的证据

Li-Fraumeni Syndrome (LFS) is caused by a germline mutation in TP53, which greatly increases the risk of earlier onset malignancies. Microbial communities can regulate the host inflammation and metabolism, linking them to p53 biology. However, we do not fully understand how gut microbiome contributes to this risk. In this study, we looked at how depleting microbiota impacts tumor development in a mouse model of LFS. Trp53 R172H/WT (LFS) mice and their wildtype (WT) littermates received a broad-spectrum antibiotic cocktail to deplete the gut microbiota. After four days of treatment, mice were injected subcutaneously with MC38 colon adenocarcinoma cells and continued the antibiotic treatment until study endpoint. LFS mice that received antibiotics developed significantly smaller tumors compared to untreated LFS controls, while the tumor growth in WT mice did not change. This suggests that microbial activity promotes tumor growth in mutant p53 mice. To interrogate if microbial metabolites, rather than live organisms, caused this effect, we transferred filtered fecal matter from LFS mice to WT recipients. These filtrates increased tumor size, showing that soluble microbial products can mimic the tumor-promoting effect. Faecal filtrate was analyzed with LC-MS and untreated LFS mice showed higher levels of fecal bile acids compared to WT animals. The presence of these bile acids also positively correlated with subcutaneous tumor mass, and antibiotic treatment reduced bile acid presence. We observed increased NF-κB levels in the intestines of untreated LFS mice. ELISAs further confirmed elevated intestinal pro-inflammatory cytokines expression, including IL-6, TNF-alpha, IFN-gamma, and IL-17A, which decreased after microbiota depletion. In addition to these intestinal changes, untreated LFS mice had higher total levels of circulating plasma pro-inflammatory cytokines, which slightly decreased after antibiotic treatment. FITC-dextran assays demonstrated increased gut permeability in untreated LFS mice, returning to normal after treatment with antibiotics. Mutant p53 has been reported to enhance the mevalonate pathway, leading to increased cholesterol synthesis and an expanded pool of primary bile acids. These bile acids can then be converted by gut microbiota into secondary bile acids that have known inflammatory and NF-κB-activating effects. This combined metabolic and microbial pathway may explain the elevated bile acids and inflammatory signaling seen in LFS mice. Taken together, these data broaden the current understanding of LFS biology by revealing that tumor susceptibility is shaped not only by cell-intrinsic mutant p53 functions but also by microbiota-driven metabolic and inflammatory cues. This integrated view opens new avenues for therapeutic intervention beyond traditional surveillance-based care.